The diagnostic concept of schizophrenia: its history, evolution, and future prospects.

More than a century since the delineation of dementia praecox by Kraepelin, the etiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Despite the availability of criteria allowing reliable diagnostic identification, schizophrenia essentially remains a broad clinical syndrome defined by reported subjective experiences (symptoms), loss of function (behavioral impairments), and variable patterns of course. Research has identified a number of putative biological markers associated with the disorder, including neurocognitive dysfunction, brain dysmorphology, and neurochemical abnormalities. Yet none of these variables has to date been definitively proven to possess the sensitivity and specificity expected of a diagnostic test. Genetic linkage and association studies have targeted multiple candidate loci and genes, but failed to demonstrate that any specific gene variant, or a combination of genes, is either necessary or sufficient to cause schizophrenia. Thus, the existence of a specific brain disease underlying schizophrenia remains a hypothesis. Against a background of an ever-increasing volume of research data, the inconclusiveness of the search for causes of the disorder fuels doubts about the validity of the schizophrenia construct as presently defined. Given the protean nature of the symptoms of schizophrenia and the poor coherence of the clinical and biological findings, such doubts are not without reason. However, simply dismantling the concept is unlikely to result in an alternative model that would account for the host of clinical phenomena and research data consistent with a disease hypothesis of schizophrenia. For the time being, the clinical concept of schizophrenia is supported by empirical evidence that its multiple facets form a broad syndrome with non-negligible internal cohesion and a characteristic evolution over time. The dissection of the syndrome with the aid of endophenotypes is beginning to be perceived as a promising approach in schizophrenia genetics.